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Wolfgang Schuette,1 Claus-Peter Schneider,2,3 Walburga Engel-Riedel,4 Christian Schumann,5,6 Martin Kohlhaeufl,7 Monika Heidi Ursel Serke,8 Gert Hoeffken,9 Cornelius Kortsik,10 Martin Reck11 1Department of Internal Medicine II, Hospital Martha-Maria Halle-Doelau, Halle, 2Department of Pneumonology, Central Hospital, Bad Berka, 3Department of Internal Medicine, DRK Manniske Hospital, Bad Frankenhausen, 4Cologne Clinics, Merheim Lung Hospital, Cologne, 5Pneumonology, Department of Internal Medicine II, University Hospital Ulm, 6Clinic for Pneumology, Thoracic Oncology, Sleep, and Respiratory Critical Care, Kempten-Oberallgäu, 7Center of Pneumonology and Chest Surgery, Hospital Schillerhoehe, Gerlingen, 8Pneumonology, Lung Clinics, Hemer, 9Center of Pneumonology, Chest and Vascular Surgery, Specialty Hospital Coswig, Coswig, 10Department of Pneumonology, Catholic Hospital, Mainz, 11Department of Thoracic Oncology, Lung Clinic, Grosshansdorf, Germany Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC).Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS).Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0–1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03–1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195–2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS.Conclusion: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0–1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy. Keywords: bevacizumab, pemetrexed, carboplatin, NSCLC, elderly patients

Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of (177)Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by (18)F-FDG and (68)gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up PET/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and (68)Ga-somatostatin-receptor PET/CT in the management of MCC. [ABSTRACT FROM AUTHOR]

Introduction: Poor oral hygiene can cause infections and inflammatory diseases. Data on its impact on outcome after lung transplantation (LuTX) is scarce. Most transplant centers have individual standards regarding dental care as there is no clinical guideline. This study's objective was to assess LuTX-listed patient's dental status and determine its effect on postoperative outcome., Methods: Two hundred patients having undergone LuTX from 2014 to 2019 were selected. Collected data comprised LuTX-indication, periodontal status, and number of carious teeth/fillings. A preoperative panoramic dental X-ray and a dentist's consultative clarification were mandatory., Results: 63.5% had carious dental status, differing significantly regarding TX-indication (p < 0.001; ILD: 41.7% vs. CF: 3.1% of all patients with carious teeth). Mean age at the time of LuTX differed significantly within these groups. Neither preoperative carious dental status nor periodontitis or bone loss deteriorated post-LuTX survival significantly. No evidence was found that either resulted in a greater number of deaths related to an infectious etiology., Conclusion: This study shows that carious dental status, periodontitis, and bone loss do not affect post-TX survival. However, literature indicates that they can cause systemic/pulmonary infections that deteriorate post-LuTX survival. Regarding the absence of standardized guidelines regarding dental care and LuTX, we strongly recommend emphasizing research in this field., (© 2023 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

Molecular matching is a new approach for virtual histocompatibility testing in organ transplantation. The aim of our study was to analyze whether the risk for de novo donor-specific HLA antibodies (dnDSA) after lung transplantation (LTX) can be predicted by molecular matching algorithms (MMA) and their combination. In this retrospective study we included 183 patients undergoing LTX at our center from 2012-2020. We monitored dnDSA development for 1 year. Eplet mismatches (epMM) using HLAMatchmaker were calculated and highly immunogenic eplets based on their ElliPro scores were identified. PIRCHE-II scores were calculated using PIRCHE-II algorithm (5- and 11-loci). We compared epMM and PIRCHE-II scores between patients with and without dnDSA using t-test and used ROC-curves to determine optimal cut-off values to categorize patients into four groups. We used logistic regression with AIC to compare the predictive value of PIRCHE-II, epMM, and their combination. In total 28.4% of patients developed dnDSA (n = 52), 12.5% class I dnDSA (n = 23), 24.6% class II dnDSA (n = 45), and 8.7% both class II and II dnDSA (n = 16). Mean epMMs (p-value = 0.005), mean highly immunogenic epMMs (p-value = 0.003), and PIRCHE-II (11-loci) (p = 0.01) were higher in patients with compared to without class II dnDSA. Patients with highly immunogenic epMMs above 30.5 and PIRCHE-II 11-loci above 560.0 were more likely to develop dnDSA (31.1% vs. 14.8%, p-value = 0.03). The logistic regression model including the grouping variable showed the best predictive value. MMA can support clinicians to identify patients at higher or lower risk for developing class II dnDSA and might be helpful tools for immunological risk assessment in LTX patients., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Background: COVID-19 causes a wide range of symptoms, with particularly high risk of severe respiratory failure and death in patients with predisposing risk factors such as advanced age or obesity. Recipients of solid organ transplants, and in particular lung transplantation, are more susceptible to viral infection owing to immune suppressive medication. As little is known about the SARS-CoV-2 infection in these patients, this study was undertaken to describe outcomes and potential management strategies in early COVID-19 infection early after lung transplantation., Methods: We describe the incidence and outcome of COVID-19 in a cohort of recent lung transplant recipients in Munich. Six of 186 patients who underwent lung transplantation in the period between March 2019 and March 2021 developed COVID-19 within the first year after transplantation. We documented the clinical course and laboratory changes for all patients showing differences in the severity of the infection with COVID-19 and their outcomes., Results: Three of 6 SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment after lung transplantation. All patients suffered from symptoms. One patient did not receive antiviral therapy. Remdesivir was prescribed in 4 patients and the remaining patient received remdesivir, bamlanivimab and convalescent plasma., Conclusions: COVID-19 does not appear to cause milder disease in lung transplant recipients compared with the general population. Immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss. Several comorbidities and a general poor preoperative condition showed an extended hospital stay., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Most SCLC patients are diagnosed with extensive disease (ED) and the prognosis in this cohort remains poor. However, some patients are diagnosed with limited (LD) or very limited (VLD, T1-2, N0-1, M0) disease and previous data suggest that surgical resection might improve outcomes in these patients. Most of the existing evidence comes from small case series. For this reason, we investigated clinical features and surgical outcomes in a large cohort of resected SCLC patients., Patients and Methods: We used a large pseudomized dataset (n = 32432) provided by the Munich Cancer Registry to analyze all documented SCLC patients (n = 5043) between 2002 and 2015. We correlated patients' characteristics as well as surgery modalities with survival data and describe trends in the role of surgery in SCLC over the time., Results: We analyzed 5043 SCLC patients. A total of 161 (3.2%) received either oncological (lobectomy, bilobectomy and pneumonectomy) or limited resection (segmentectomy and wedge resection). We found a significant trend suggesting that resections in SCLC patients become less common in all stages of disease, accompanied by an increased proportion of oncological resections. This suggests a more accurate preoperative staging. In VLD resection was significantly associated with longer survival compared to nonsurgical management (log-rank P = .013). Survival was better with oncological resection compared to atypical resection. Administration of adjuvant chemotherapy was associated with better outcome in all resected patients (P = .01)., Conclusion: VLD SCLC patients benefit from oncological resection. We recommend invasive staging in these patients to ensure VLD. Furthermore, adjuvant chemotherapy should be offered to all resected patients., (Copyright © 2022. Published by Elsevier Inc.)

Autologous fillet flaps are a common reconstructive option for large defects after forequarter amputation (FQA) due to advanced local malignancy or trauma. The inclusion of osseous structures into these has several advantages. This article therefore systematically reviews reconstructive options after FQA, using osteomusculocutaneous fillet flaps, with emphasis on personalized surgical technique and outcome. Additionally, we report on a case with an alternative surgical technique, which included targeted muscle reinnervation (TMR) of the flap. Our literature search was conducted in the PubMed and Cochrane databases. Studies that were identified were thoroughly scrutinized with regard to relevance, resulting in the inclusion of four studies (10 cases). FQA was predominantly a consequence of local malignancy. For vascular supply, the brachial artery was predominantly anastomosed to the subclavian artery and the brachial or cephalic vein to the subclavian or external jugular vein. Furthermore, we report on a case of a large osteosarcoma of the humerus. Extended FQA required the use of the forearm for defect coverage and shoulder contour reconstruction. Moreover, we performed TMR. Follow-up showed a satisfactory result and no phantom limb pain. In case of the need for free flap reconstruction after FQA, this review demonstrates the safety and advantage of osteomusculocutaneous fillet flaps. If the inclusion of the elbow joint into the flap is not possible, we recommend the use of the forearm, as described. Additionally, we advocate for the additional implementation of TMR, as it can be performed quickly and is likely to reduce phantom limb and neuroma pain.

The deposition of highly ordered fibrillar-type aggregates into inclusion bodies is a hallmark of neurodegenerative diseases such as Parkinson's disease. The high stability of such amyloid fibril aggregates makes them challenging substrates for the cellular protein quality-control machinery 1,2 . However, the human HSP70 chaperone and its co-chaperones DNAJB1 and HSP110 can dissolve preformed fibrils of the Parkinson's disease-linked presynaptic protein α-synuclein in vitro 3,4 . The underlying mechanisms of this unique activity remain poorly understood. Here we use biochemical tools and nuclear magnetic resonance spectroscopy to determine the crucial steps of the disaggregation process of amyloid fibrils. We find that DNAJB1 specifically recognizes the oligomeric form of α-synuclein via multivalent interactions, and selectively targets HSP70 to fibrils. HSP70 and DNAJB1 interact with the fibril through exposed, flexible amino and carboxy termini of α-synuclein rather than the amyloid core itself. The synergistic action of DNAJB1 and HSP110 strongly accelerates disaggregation by facilitating the loading of several HSP70 molecules in a densely packed arrangement at the fibril surface, which is ideal for the generation of 'entropic pulling' forces. The cooperation of DNAJB1 and HSP110 in amyloid disaggregation goes beyond the classical substrate targeting and recycling functions that are attributed to these HSP70 co-chaperones and constitutes an active and essential contribution to the remodelling of the amyloid substrate. These mechanistic insights into the essential prerequisites for amyloid disaggregation may provide a basis for new therapeutic interventions in neurodegeneration.

Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient-derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Biotherapeutics are the fastest growing class of pharmaceutical with a rapidly evolving market facing the rise of biosimilar and biobetter products. In contrast to a biosimilar, which is derived from the same gene sequence as the innovator product, a biobetter has enhanced properties, such as enhanced efficacy or reduced immunogenicity. Little work has been carried out so far to increase the intrinsic stability of biotherapeutics via sequence changes, even though, aggregation, the primary degradation pathway of proteins, leads to issues ranging from manufacturing failure to immunological response and to loss of therapeutic activity. Using our spatial aggregation propensity tool as a first step to a rational design approach to identify aggregation-prone regions, biobetters of rituximab have been produced with enhanced stability by introducing site-specific mutations. Significant stabilization against aggregation was achieved for rituximab with no decrease in its binding affinity to the antigen., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

RNA-mediated gene silencing in human cells requires the accurate generation of ∼22 nt microRNAs (miRNAs) from double-stranded RNA substrates by the endonuclease Dicer. Although the phylogenetically conserved RNA-binding proteins TRBP and PACT are known to contribute to this process, their mode of Dicer binding and their genome-wide effects on miRNA processing have not been determined. We solved the crystal structure of the human Dicer-TRBP interface, revealing the structural basis of the interaction. Interface residues conserved between TRBP and PACT show that the proteins bind to Dicer in a similar manner and by mutual exclusion. Based on the structure, a catalytically active Dicer that cannot bind TRBP or PACT was designed and introduced into Dicer-deficient mammalian cells, revealing selective defects in guide strand selection. These results demonstrate the role of Dicer-associated RNA binding proteins in maintenance of gene silencing fidelity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Afatinib, an irreversible ErbB family blocker, demonstrated superiority to chemotherapy as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Afatinib is also active in patients progressing on EGFR tyrosine kinase inhibitors (EGFR-TKIs). We report the results of a large cohort of NSCLC patients receiving afatinib within a compassionate-use program (CUP)., Patients and Methods: Patients with advanced NSCLC progressing after one line or more of chemotherapy and one line or more of EGFR-TKI treatment with either an EGFR mutation or documented clinical benefit were enrolled. Data collection was not monitored or verified by central review. The intention of this CUP was to provide controlled preregistration access to afatinib for patients with life-threatening diseases and no other treatment option., Results: From May 2010 to October 2013, 573 patients (65% female; median age: 64 years [range: 28-89 years]) were enrolled, with strong participation of community oncologists. Comorbidities were allowed, including second malignancies in 11% of patients. EGFR mutation status was available in 391 patients (72%), and 83% tested mutation positive. Median time to treatment failure (TTF) of 541 patients treated with afatinib was 3.7 months (range: 0.0 to >29.0 months). Median TTF was 4.0 and 2.7 months in patients with adenocarcinomas and squamous cell carcinomas, respectively, and 4.6 months in patients with EGFR-mutated NSCLC. Adverse events were generally manageable., Conclusion: Afatinib was able to be given in a real-world setting to heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC. Acknowledging the constraints of data collection in a CUP, afatinib appears to be safe and to confer some clinical benefit in this population., (©AlphaMed Press.)

Objective: To determine analgesic effects of intraneural injection of ethyl alcohol or formaldehyde in the palmar digital nerves of horses., Animals: 6 horses., Procedures: Ethyl alcohol was injected in the medial palmar digital nerve of 1 forelimb, and formaldehyde was injected in the contralateral nerve. The lateral palmar digital nerve in 1 forelimb was surgically exposed, but not injected, and the contralateral lateral palmar digital nerve was not treated. For each heel, severity of lameness in response to experimentally induced heel pain (lameness score and peak vertical force), thermal reaction time, and heel skin sensitivity scores were recorded. Heel pain was experimentally induced by advancing a threaded bolt through a custom-made horseshoe to apply pressure to the palmar horned aspect of the hoof. Horses were followed up for 112 days, when a subset of nerves was sampled for histologic analysis., Results: Alcohol and formaldehyde significantly reduced all measures of heel pain, and analgesia was evident over the 112 days of the study. Pastern circumference was significantly greater for formaldehyde-treated than for alcohol-treated limbs. Histologic evaluation showed preservation of nerve fiber alignment with an intact epineurium, loss of axons, axon degeneration, fibrosis, and inflammation in alcohol-treated and formaldehyde-treated nerves., Conclusions and Clinical Relevance: Results suggested that intraneural injection of either ethyl alcohol or formaldehyde in the palmar digital nerves of horses resulted in substantial, but partial, heel analgesia that persisted for at least 112 days. No advantage of formaldehyde over alcohol was found, and formaldehyde resulted in greater soft tissue inflammation.

Introduction: The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol. 2012;30:2829-2836). Herein, we report data from the squamous cohort., Methods: Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/mL•min/paclitaxel, 200 mg/m) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival., Results: Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months)., Conclusions: Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC.

Background: The immune balance controlled by T-helper (Th)1 and Th2 cells is critical in protecting the host from pathogenic invasion, and its imbalance may increase susceptibility to infection in patients undergoing major surgery. The differentiation of naive T cells to Th1 and Th2 cells is largely driven by cytokines. In addition, steroid hormones have been shown to affect Th1/Th2 balance, particularly in autoimmune diseases. The regulation of Th1/Th2 balance in patients undergoing surgery and its potential clinical relevance remain unclear., Materials and Methods: Blood samples were obtained from patients both before and 2 h after major abdominal surgery. Peripheral blood mononuclear cells were isolated and cultured in wells coated with either anti-CD3 (direct T-cell stimulation) or phytohemagglutinin (PHA) (indirect T-cell stimulation), with or without 10(-5) M dehydroepiandrosterone (DHEA). The release of interleukin (IL)-2, interferon gamma, and IL-10 was measured by an enzyme-linked immunosorbent assay, and the expression of CD4, CD8, and CD69 was determined by flow cytometry., Results: DHEA decreased the release of IL-2 and IL-10 in directly (anti-CD3) and indirectly (PHA)-stimulated T cells from postoperative samples, whereas the release of interferon gamma in PHA-stimulated T cells was not affected. The distribution of CD4/CD8 was not significantly different after surgery or DHEA. DHEA was associated with a decrease in the expression of the activation marker CD69 on CD4(+) T cells, whereas the activation of CD8(+) T cells remained unchanged., Conclusions: These results demonstrate that DHEA plays a critical role in controlling Th1/Th2 balance in the immediate postoperative period. Attenuation of both the Th1 and Th2 responses has been suggested to have immunoprotective effects. The role of DHEA in the regulation of Th1/Th2 balance in patients undergoing major abdominal surgery may, therefore, also be of significant clinical relevance and warrants further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) isoform is an unfavorable prognostic factor in non-small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including β3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for β3T expression., Patients and Methods: Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup., Results: Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies., Conclusion: There was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.

Purpose: We wanted to identify the importance of the duration of invasive ventilation and of renal replacement therapy for short-term prognosis of surgical patients treated in an intensive care unit (ICU)., Methods: We analyzed adult patients (n = 1462) who had an ICU length of stay of more than 4 days and who were followed up until the end of the short-term phase after ICU admission. Duration of different invasive therapies was evaluated by constructing specific vectors that tested effects of time-dependent variables on outcome after a lag time of 7 days., Measurements and Main Results: Eight hundred eight patients (56.6%) were still alive at the end of the short-term phase. During the short-term phase, 85.3% of the 1462 patients required invasive ventilation, and 16.1%, a continuous renal replacement therapy. Besides the underlying disease and disease severity at ICU admission, the need for invasive ventilation or renal replacement therapy was associated with poorer outcome. Duration of invasive ventilation shortened survival if treatment lasted for more than 11 days (nonlinear association). In contrast, duration of renal replacement therapy was unimportant for short-term prognosis., Conclusion: Prolonged duration of invasive ventilation but not of renal replacement therapy is inversely related to short-term survival., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study., Patients and Methods: Patients with advanced-stage non-small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate., Results: In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo., Conclusion: The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR.

Protein stability in ionic solutions depends on the delicate balance between protein-ion and ion-ion interactions. For molecular ions containing multiple charged groups, the role of ion-ion interactions is particularly important. In this study, we show how the interplay between homo- and heteroion pairing influences protein stability using polyarginine salts as a model system. For the chloride salts, protein thermostability decreases as the size of the peptide increases, indicating enhanced binding to the protein. Moreover, it indicates reduced homoion pairing between Gdm(+) and carboxylate groups that is largely responsible for aggregation suppression, rather than denaturation, in monomeric arginine solutions. However, for the sulfate salts, strong heteroion pairing between the Gdm(+) groups and the sulfate counterions compensates for the loss of homoion pairing and, in return, leads to enhanced thermostability and a dramatically reduced (up to 10-30 times) rate of protein aggregation. Molecular dynamics simulations reveal how this ion pairing enhances conformational stability and, at the same time, reduces protein association. This study provides insight into complex ion effects on protein stability and serves as an example of how these intrasolvent interactions can be leveraged to enhance protein stability.

Protein based therapeutics hold great promise in the treatment of human diseases and disorders and subsequently, they have become the fastest growing sector of new drugs being developed. Proteins are, however, inherently unstable and the degraded form can be quite harmful if administered to a patient. Of the various degradation pathways, aggregation is one of the most common and a cause for great concern. Aggregation suppressing additives have long been used to stabilize proteins, and they still remain the most viable option for combating this problem. Much work has been devoted toward investigating the behavior of commonly used additives and the resulting models give valuable insight toward explaining aggregation suppression. In a few cases, an explanation for unique behavior is lacking or new insight provides an alternate explanation. Additive selection and the development of better performing additives may benefit from a more refined understanding of how commonly used additives inhibit or enhance aggregation. In this review, we focus on recent molecular-level studies into how a select group of commonly used additives interact with proteins and subsequently influence aggregation. The intent of the review is not meant to be comprehensive for each additive but rather to provide new insights into additive-additive interactions, which may be contributing to protein-additive interactions. This is something that is often overlooked but yet essential to understanding the effect of additives on aggregation. The importance of understanding such interactions is clear when one considers that most formulations contain a mixture of cosolutes and that ideal stability might be better achieved through tuning intra-solvent interactions. We give an example of this when we describe how novel aggregation suppressing additives were developed from the knowledge gained from the reviewed studies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Neuroendocrine tumors are heterogeneous in their clinical behavior and require therapies specially tailored according to staging and grading, origin and expression of peptide receptors. Somatostatin analogues act as antisecretory and antiproliferative agents. Chemotherapy is mandatory for poorly differentiated neuroendocrine carcinomas and is also effective in neuroendocrine tumors of the pancreas and of the bronchial system. For localized neuroendocrine tumors, surgery should be performed with curative intent and is also an option in advanced or metastasized neuroendocrine tumors with the goal to debulk tumor masses. Local ablative therapies may be applied to decrease tumor load in the liver; however, results are often of short duration. Peptide receptor radiotherapy is a new treatment method applying radionuclide-targeted somatostatin receptor agonists for internal cytotoxic radiotherapy in somatostatin receptor-expressing neuroendocrine tumors. Retrospective and prospective clinical studies indicate prolonged progression-free survival and overall survival of patients responding by stable disease or any kind of remission with this innovative treatment, which is, however, available only in a few specialized centers. Finally, small-molecule inhibitors of vascular endothelial growth factor and serine/threonine-protein kinase mTOR pathways have been shown to delay progression in patients with neuroendocrine tumors. In summary, treatment options for neuroendocrine tumors have expanded considerably in the last years leading to prolonged overall survival., (Copyright 2011 Prous Science, S.A.U. or its licensors. All rights reserved.)

L-Arginine hydrochloride is a very important aggregation suppressor for which there has been much attention given regarding elucidating its mechanism of action. Little consideration, however, has been given toward other salt forms besides chloride, even though the counterion likely imparts a large influence per the Hofmeister Series. Here, we report an in depth analysis of the role the counterion plays in the aggregation suppression behavior of arginine. Consistent with the empirical Hofmeister series, we found that the aggregation suppression ability of other arginine salt forms on a model protein (α-chymotrypsinogen) follows the order: H(2)PO(4)(-) > SO(4)(2-) > citrate(2-) > acetate(-) ≈ F(-) ≈ Cl(-) > Br(-) > I(-) ≈ SCN(-). Mechanistically, preferential interaction and osmotic virial coefficient measurements, in addition to molecular dynamics simulations, indicate that attractive ion-ion interactions, particularly attractive interactions between arginine molecules, play a dominate role in the observed behavior. Furthermore, it appears that dihydrogen phosphate, sulfate, and citrate have strong attractive interactions with the guanidinium group of arginine, which seems to contribute to the superior aggregation suppression ability of those salt forms by bridging together multiple arginine molecules into clusters. These results not only further our understanding of how arginine influences protein stability, they also help to elucidate the mechanism behind the Hofmeister Series. This should help to improve biopharmaceutical stabilization through the use of other arginine salts and possibly, the development of novel excipients.

Much work has been performed on understanding the effects of additives on protein thermodynamics and degradation kinetics, in particular addressing the Hofmeister series and other broad empirical phenomena. Little attention, however, has been paid to the effect of additive-additive interactions on proteins. Our group and others have recently shown that such interactions can actually govern protein events, such as aggregation. Here we use dendrimers, which have the advantage that both size and surface chemical groups can be changed and therein studied independently. Dendrimers are a relatively new and broad class of materials which have been demonstrated useful in biological and therapeutic applications, such as drug delivery, perturbing amyloid formation, etc. Guanidinium modified dendrimers pose an interesting case given that guanidinium can form multiple attractive hydrogen bonds with either a protein surface or other components in solution, such as hydrogen bond accepting counterions. Here we present a study which shows that the behavior of such macromolecule species (modified PAMAM dendrimers) is governed by intra-solvent interactions. Attractive guanidinium-anion interactions seem to cause clustering in solution, which inhibits cooperative binding to the protein surface but at the same time, significantly suppresses nonnative aggregation.

Objective: To identify the prognostic importance of preceding invasive ventilation, renal replacement therapy, and catecholamine therapy for long-term survivors after surgical critical illness., Summary Background Data: Nothing is known about the effect of preceding intensive care unit (ICU)-related therapies on long-term outcome., Methods: We performed a retrospective analysis of prospectively collected data of an ICU patient cohort linked to a local database. Adult patients (n = 1462) admitted to a 12-bed ICU between 1993 and 2005, who had an ICU length of stay of more than 4 days, were followed up until the end of the second year after ICU admission. Hazard function was explored by Weibull modeling and likelihood ratio tests. Cox-type structured hazard regression models were used to analyze linear, nonlinear, or time-varying associations of therapeutic variables with 2-year survival time of a patient subgroup, which had survived the period of high hazard., Results: Hazard rate declined exponentially up to day 195 after ICU admission, and became constant thereafter. A total of 808 patients reached this stable stage of their disease forming the study population. Of these patients, 648 (80.2%) were still alive at the end of the second year after ICU admission. Underlying diseases were major determinants for long-term outcome. Long-term mortality was significantly associated with the acute extent of physiological derangement during ICU stay (maximum Apache II score), but was independent from the duration of preceding invasive organ support., Conclusion: In surgical patients with a prolonged ICU length of stay, an exorbitant mortality exists for about half a year after ICU admission. Later on, life expectancy of surviving patients is largely determined by the underlying disease and, to a minor degree, by the acute extent of homeostatic disturbance during ICU stay. The duration of preceding invasive therapies does not limit long-term survival.